US2006101532A1PendingUtilityA1

Methods for the identification of compounds for the treatment of Alzheimer's disease

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Individually held — no corporate assignee on recordPriority: Apr 30, 1999Filed: Nov 8, 2004Published: May 11, 2006
Est. expiryApr 30, 2019(expired)· nominal 20-yr term from priority
Inventors:Ralph A. NixonAnne M. CataldoPaul Mathews
A01K 67/0275G01N 33/6896C12N 9/14G01N 2800/2821C07K 14/72C07K 14/4711A01K 2267/0318G01N 2500/10A01K 2217/05G01N 2333/916C12N 2830/008C12N 15/85C12N 9/6478A01K 2227/105C07K 14/705A01K 67/027C07K 14/47A01K 2267/0312C12N 9/64C12N 15/8509
42
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Claims

Abstract

The invention features methods for identifying compounds useful for the treatment of Alzheimer's disease. The invention also features methods of identifying genes involved in Alzheimer's disease pathology.

Claims

exact text as granted — not AI-modified
1 . A method for identifying a candidate compound as a compound that is useful for the treatment of Alzheimer's disease, said method comprising the steps of: 
 (a) providing a Tn65Dn mouse;    (b) administering a candidate compound to said mouse; and    (c) measuring the activity of the endocytic pathway, wherein a decrease in said activity, compared to the activity in a Tn65Dn mouse not contacted with said candidate compound, identifies said candidate compound as a compound that is useful for the treatment of Alzheimer's disease.    
     
     
         2 . The method of  claim 1 , wherein said activity of the endosomal pathway is selected from the group consisting of endosomal fusion, endosomal recycling, expression of MPR46, accumulation of lysosomal hydrolases in early endosomes, and accumulation of AP in early endosomes.  
     
     
         3 . A method for identifying a candidate compound as a compound that is useful for the treatment of Alzheimer's disease, said method comprising the steps of: 
 (a) providing a Tn65Dn mouse;    (b) administering a candidate compound to said mouse; and    (c) measuring AP formation, wherein a decrease in said Aβ formation, compared to Aβ formation in a Tn65Dn mouse not contacted with said candidate compound, identifies said candidate compound as a compound that is useful for the treatment of Alzheimer's disease.    
     
     
         4 . A method for identifying a candidate compound as a compound that is useful for the treatment of Alzheimer's disease, said method comprising the steps of: 
 (a) providing a cell from a Tn65Dn mouse or a cell from a human with trisomy 21;    (b) contacting said cell with the candidate compound; and    (c) measuring the activity of the endocytic pathway, wherein a normalization in said activity, compared to the activity in a control cell not contacted with said candidate compound, identifies the candidate compound as a compound that is useful for the treatment of Alzheimer's disease.    
     
     
         5 . The method of  claim 4 , wherein said activity of the endosomal pathway is selected from the group consisting of endosomal fusion, endosomal recycling, expression of MPR46, accumulation of lysosomal hydrolases in early endosomes, and accumulation of Aβ in early endosomes.  
     
     
         6 . The method of  claim 4 , wherein said cell is from a cell line derived from said mouse or said human.  
     
     
         7 . The method of  claim 6 , wherein said cell line is selected from the group consisting of a fibroblast cell line, a neuronal cell line, and a neuroblastoma cell line.  
     
     
         8 . The method of  claim 4 , wherein said cell is selected from the group consisting of a fibroblast, a neuron, and an endothelial cell.  
     
     
         9 . The method of  claim 4 , wherein said cell is in vitro.  
     
     
         10 . A method for identifying a candidate compound as a compound that is useful for the treatment of Alzheimer's disease, said method comprising the steps of: 
 (a) providing a cell from a Tn65Dn mouse or a cell from a human with trisomy 21;    (b) contacting said cell with the candidate compound; and    (c) measuring Aβ formation, wherein a decrease in said Aβ formation, compared to Aβ formation in a control cell not contacted with said candidate compound, identifies the candidate compound as a compound that is useful for the treatment of Alzheimer's disease.    
     
     
         11 . The method of  claim 10 , wherein said activity of the endosomal pathway is selected from the group consisting of endosomal fusion, endosomal recycling, expression of MPR46, accumulation of lysosomal hydrolases in early endosomes, and accumulation of Aβ in early endosomes.  
     
     
         12 . The method of  claim 10 , wherein said cell is from a cell line derived from said mouse or said human.  
     
     
         13 . The method of  claim 12 , wherein said cell line is selected from the group consisting of a fibroblast cell line, a neuronal cell line, and a neuroblastoma cell line.  
     
     
         14 . The method of  claim 10 , wherein said cell is selected from the group consisting of a fibroblast, a neuron, and an endothelial cell.  
     
     
         15 . The method of  claim 10 , wherein said cell is in vitro.  
     
     
         16 . A method of identifying a gene as a gene involved in Alzheimer's disease pathology, said method comprising the steps of: 
 (a) providing a cell from a Tn65Dn mouse or a cell from a human with trisomy 21;    (b) contacting said cell with an agent that reduces the expression of a gene that is present in said cell in three copies; and    (c) measuring the activity of the endocytic pathway, wherein a decrease in said activity, compared to the activity in a control cell not contacted with said agent, identifies the gene as a gene that a gene involved in Alzheimer's disease pathology.    
     
     
         17 . The method of  claim 16 , wherein said activity of the endosomal pathway is selected from the group consisting of endosomal fusion, endosomal recycling, expression of MPR46, accumulation of lysosomal hydrolases in early endosomes, and accumulation of AP in early endosomes.  
     
     
         18 . The method of  claim 16 , wherein said cell is from a cell line derived from said mouse or said human.  
     
     
         19 . The method of  claim 18 , wherein said cell line is selected from the group consisting of a fibroblast cell line, a neuronal cell line, and a neuroblastoma cell line.  
     
     
         20 . The method of  claim 16 , wherein said cell is selected from the group consisting of a fibroblast, a neuron, and an endothelial cell.  
     
     
         21 . The method of  claim 16 , wherein said cell is in vitro.  
     
     
         22 . The method of  claim 16 , wherein said gene is selected from the group consisting of Adamts1, Adamts5, Ankrd3, Atp5a, Atp5o, B3galt5, Bace2, Bach1, C21orf108, C21orf18, C21orf25, C21orf4, C21orf5, C21orf51, C21orf59, C21orf6, C21orf63, C21orf66, C21or7, Cbr1, Cbr3, Cct8, Chaf1b, Cldn17, Cldn8, Clic6, Cryzl1, Ctdbp, Donson, Dscam, Dscr1, Dscr2, Dscr3, Dscr5, Dyrk1a, Erg, Ets2, Fam3b, Gabpa, Gart, Grik1, Hlcs, Hmgnl, Hunk, Ifnar1, Ifnar2, Ifngr2, Igsf5, Il10rb, Itsn1, Jam2, Kcne1, Kcne2, Kcnj15, Kcnj6, Kiaa0136, Kiaa0184, Krtap11-1, Mrpl39, Mrps6, Mx1, Mx2, Olig2, Pcbp3, Pcnt2, Pcp4, Pdxk, Pjkl, Psmd4, Runx1, Sh3bgr, Sim2, Slc5a3, Sod1, Son, Synj1, Tiam1, Tmprss2, Ttc3, Usp16, Wdr9, Wrb, Znf294, and Znj295.  
     
     
         23 . The method of  claim 16 , wherein said agent is an siRNA that selectively reduces expression of said gene.

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